Neglected tropical diseases: Developing drugs for NTDs

Neglected tropical diseases (NTDs) affect the world’s poorest people, causing death, disability and prolonged disadvantage. Many of these diseases lack effective treatments but the rising profile of NTDs means more resources are becoming available for research and development. However, the challenges of finding new drugs for NTDs go beyond funding, as Michael Regnier reports in the fourth post in our NTDs series.

A handful of NTDs – schistosomiasis, trachoma and hookworm, for example – have effective drugs available for treating them. For these diseases, the challenge lies in acquiring and distributing sufficient doses to treat the millions of people suffering with them. However for many, if not most, NTDs either there are no drugs or the drugs we do have are old, cause significant side-effects, are very expensive, or are losing their potency because the parasites, viruses and bacteria that cause the diseases are developing drug resistance.

Professor Alan Fairlamb

Professor Alan Fairlamb, Co-Director of the Wellcome Trust-funded Drug Discovery Unit (DDU) at the University of Dundee, says that only a handful of NTD drugs are truly fit for purpose: “Many compounds were originally developed with a different indication in mind, maybe from cancer research or anti-fungal drug discovery programs. The target product profile for these original indications does not take into account the association with poverty and the rural setting where most NTD drugs are needed.”

The cost of new drugs is another significant issue. “Expensive drugs are good for the odd safari but too costly for the local population,” he adds. “People often can’t afford the treatment, so they don’t complete the course and this drives resistance. The challenge is to develop cheaper and safer drugs.”

The Dundee Unit works with scientists who have discovered a promising target but perhaps don’t have the know-how or the infrastructure to do drug discovery. “Our vision is to take excellent basic science and turn it into useful medical products,” explains Fairlamb. They work directly with industry and through product development partnerships such as the Drugs for Neglected Diseases Initiative (DNDi).

“The product development partnership is a good model,” says Fairlamb. “It is starting to transform the situation with respect to new drugs [for NTDs]. But there is a five-year cycle of funding, they need to demonstrate success and, understandably, are therefore slightly risk-averse to early stage drug discovery. The DDU fills this gap.”

The Unit’s most successful project to date is based on an enzyme called N-myristoyltransferase (NMT), which was developed as a target for new drugs to treat leishmaniasis and other diseases at Imperial College London by Professor Deborah Smith, now at the University of York.

Journey of drug discovery

“We sequenced genes from Leishmania parasites transmitted by sand flies and screened for molecules produced exclusively in the infective stage of their life cycle,” Smith explains. “We found one molecule that had to undergo a specific modification in order to be presented on the surface of the parasite cells. That modification was catalysed by NMT, which we knew had been previously developed by Pfizer as a drug target for fungal pathogens.”

Although Pfizer had developed inhibitors of NMT, they were each specific to particular species of fungus. Doctors would have had to identify the type of fungus infecting their patient before treating them with the right NMT inhibitor. Because fungal infections can be difficult to distinguish, Pfizer had instead turned its attention to developing general antifungal drugs that would work against multiple species.

Knowing that Pfizer had already worked on NMT meant Smith and her colleagues could be confident that it was a strong candidate for development. The specificity of NMT inhibitors would be less of a problem because, while there are different species of parasite that cause leishmaniasis, they cause distinctly different symptoms in different parts of the world.

Smith persuaded Pfizer to share some of their compounds for her research to confirm that NMT is vital to Leishmania parasites. Then she discovered that the enzyme is also found in the parasites that cause human African trypanosomiasis (sleeping sickness) and may even be a target in Plasmodium, the parasite that causes malaria.

Professor Deborah Smith

“Will one key enzyme be a target for multiple parasites? There’s still a long way to go,” says Smith. Even if the work on NMT does not lead to a viable drug for all these diseases, however, it will be valuable research. “We’re doing the groundwork for future potential opportunities,” she concludes.

A large consortium is now working on drugs to target NMT in the various diseases. Work on human African trypanosomiasis is being led by the Dundee Drug Discovery Unit, while Smith is leading work on leishmaniasis and Plasmodium in York in collaboration with colleagues at Imperial College London, the Medical Research Council National Institute for Medical Research in London, and the University of Nottingham.

Safeguarding treatments

Professor Paul Kaye, Director of the Centre for Immunology and Infection at the University of York, has been doing research into leishmaniasis for many years and knows that new targets like NMT are rare and clinical trials even more so. “Poverty is a major driver both in the disease and in limiting investment,” he says. “We don’t have the money to do iterative testing as in other diseases. Malaria has seen 20 to 30 trials in recent years, whereas we’re seeing the first clinical trial in leishmaniasis to be funded in ten years.” As with all NTDs, it is crucial to keep pursuing other avenues of research.

Professor Paul Kaye

For example, Kaye and Smith are working together on developing a therapeutic vaccine for leishmaniasis, targeting a different arm of the immune system to that focused on by most previous research (CD8 rather than CD4 T cells) and using new vectors to deliver the vaccine. It is one of just two second-generation vaccines in development for leishmaniasis and they hope to start phase I trials this year.

“We need to protect the drugs we have,” says Kaye. “We only have three leishmaniasis drugs and there is already resistance to the commonest drug in parts of India where visceral leishmaniasis is endemic. Second-line drugs are being used but while these are very effective, they do have some side-effects and are costly. A therapeutic vaccine given in combination could help protect the drugs’ lifetimes. Also, we could use lower doses or a lower number of doses or expect greater compliance, which would all help to minimise resistance.”

Underpinning this work are years of basic research. Kaye himself has spent 25 years looking at the fundamental immunology of why chronic disease develops from some leishmaniasis infections and not others. “Most people are well-protected and don’t show any symptoms,” he says. “What makes others susceptible?”

Smith’s postdoctoral research was in molecular biology, looking at the control of gene expression in Drosophila (fruit flies). “I became interested in the potential for applying the tools I was using in fruit flies to sand flies and the parasites they carry,” she explains. “We are basic, fundamental biologists working on pathogenic organisms. Our long-term goal is to have an impact on human disease, work that is desperately needed. We’ve been to these countries and are aware of the constant and continuing challenge these diseases present.”

Update: 2 February 2012

In addition to the NMT project described in this piece, the Drug Discovery Unit and colleagues at the University of Dundee have been working on other potential drugs for treating leishmaniasis. Yesterday, they published a paper in Science Translational Medicine (see Wyllie et al reference below), in which they describe studies on a drug called fexinidazole and conclude that it shows strong potential as a treatment for visceral leishmaniasis. The full story is on the Wellcome Trust website but it is particularly interesting because fexinidazole is an old drug that has been recently used in early clinical trials as a treatment for human African trypanosomiasis.

If fexinidazole lives up to its promise, its development as a treatment will be faster because of the work already done on it for trypanosomiasis. In the research paper, the authors quote the noted pharmacologist Sir James Black as saying that the most fruitful basis for the discovery of a new drug is to start with an old drug. Professor Fairlamb, lead author, says the adage is “particularly apt in the search for effective drugs to treat neglected tropical diseases such as visceral leishmaniasis”.

Thank you for this interesting article. The example of human african trypanosomiasis (HAT – sleeping sickness) is very relevant: drugs that are currently used are fairly old (pentamidine for stage 1 HAT dates from 1941). The current mainstay of stage 2 HAT (NECT) is made of a combination of drugs that were repurposed from other initial indications. Tools are not perfect (NECT requires 14 IV infusions) and they require specialised teams. DNDi and FIND need more support to bring their HAT pipeline products to maturation. Their objectives are: a radically simplified diagnostic tree, and an oral safe treatment for both stages. In the meantime, until new tools are available, there is no other option than increased support to specialised HAT mobile screening and treatment teams. The current downward trend in numbers of reported cases (from 26,000 in 2000 to 7,200 in 2010) can be continued. Blind spots in central Africa (foci that are alleged to be active – but are not covered yet by screening campaigns) now need to be targeted as well. But the withdrawal of Belgium’s funding from the DRC HAT programme is not a good signal. Stakeholders of the forthcoming NTD summit in London (Jan 30: http://www.unitingtocombatntds.org/ ) must deliver concrete commitments for all NTDs, including sleeping sickness.

Thanks for your comment, Julien. I think it really highlights what ‘neglect’ means in the context of diseases like sleeping sickness and leishmaniasis: there may already be treatments available but that doesn’t mean they are simple to deploy or will do the job forever. More options are needed.

Just today, I’ve read research from Alan Fairlamb and others describing how human exposure to naturally occurring arsenic in Bihar, India, might possibly be contributing to the reduction in efficacy of antimony-based drugs for visceral leishmaniasis there through the parasites gaining resistance to arsenic and antimony. It shows how complex the interactions between pathogen, host and environment can be and why finding a suitable long-term treatment is so challenging. The paper is open access in PLoS NTDs: http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0001227

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